The need for biodegradable polymers in emerging technologies such as tissue engineering, drug delivery, and gene therapy has been fueling a quest for novel biodegradable polymers [13-16]. In particular, biodegradable polymers with elastomeric properties have recently received attention for their potential use in the engineering of soft tissues such as blood vessel, heart valves, cartilage, tendon, and bladder, which exhibit elastic properties. Due to their long history of use in clinical applications, poly(hydroxyortho esters) such as polyglycolic acid (PGA), poly lactic acid (PLA) and copolymers thereof are often used to fabricate three-dimensional porous scaffolds to support cell attachment, proliferation, migration, and extracellular matrix synthesis. The development of a novel family of biodegradable elastomeric polymers referred to as poly(diol citrates) has been reported [1].
Tissues such as blood vessels, cartilage, ligament, and tendon have specific biomechanical requirements for successful functional tissue engineering. These tissues are often subjected to relatively large tensile or compressive forces, so it is important that synthetic scaffolds or implants intended to model such tissues have the necessary tensile strength, elasticity, and compressive modulus to withstand such forces. Ideally, the mechanical properties of the scaffold or implant would approximate those of the natural tissue it is designed to mimic. The reported tensile strength of human cartilage and ligament are 3.7-10.5 MPa and 24-112 MPa, respectively. The reported Young's modulus of cartilage and ligament are 0.7-15.3 MPa and 65-541 MPa, respectively. The reported tensile strength of human coronary arteries is 1.4-11.14 MPa.
It is well known in the art that the mechanical properties of elastomers can be enhanced by the fabrication of composites in which a second component or phase is added to the elastomeric phase. One method by which elastomers can be strengthened and stiffened is by incorporating nanoparticles into the elastomeric matrix [Lavik, E. and R. Langer, Tissue engineering: current state and perspectives. Appl Microbiol Biotechnol, 2004. 65: p. 1-8; Okada, M., Chemical syntheses of biodegradable polymers. Prog Polym Sci, 2002. 27: p. 87-133; Griffith., Polymeric Biomaterials. Acta Mater, 2000. 48: p. 263-277; MacDonald, J. Biomed. Mater. Res. A, 2005, 74, 489-496]. This is the case in the rubber industry where carbon black nanoparticles can be added to greatly increase the mechanical properties [Lavik, E. and R. Langer, Tissue engineering: current state and perspectives. Appl Microbiol Biotechnol, 2004. 65: p. 1-8]. The nanoparticles act as additional crosslink points to reinforce the network chains and in general, the increase in mechanical properties is inversely proportional to the nanoparticle diameter [Lavik, E. and R. Langer, Tissue engineering: current state and perspectives. Appl Microbiol Biotechnol, 2004. 65: p. 1-8]. Although this method has been used for industrial applications, there have been no reports involving the use of biocompatible, biodegradable nanoparticles to strengthen matrices intended for in vivo use.
Poly(hydroxyortho esters) or other polymers have been mixed with ceramics, glass microparticles, glass nanoparticles, glass nanofibers, or carbon nanotubes to strengthen scaffolds for bone tissue engineering applications and, to a lesser extent, for soft tissue regeneration. However, most of these approaches introduce inorganic and non-biodegradable components into the polymer composite. A non-degradable second phase may interfere with the body's natural remodeling mechanisms as the continuous presence of a foreign material may induce long-term inflammatory responses. Furthermore, the resulting composite does not exhibit the elasticity and flexibility that is important for soft tissue engineering.
Chun et al (U.S. patent application Ser. No. 10/383,369) and Melican et al (U.S. patent application Ser. No. 09/747,489) disclose tissue implants comprising a biodegradable mesh reinforcement component and a biodegradable elastomeric foam component. Ma et al (U.S. Pat. No. 6,146,892) disclose three-dimensional biodegradable matrices comprised of nanofibers. However, Chun et al, Melican et al, and Ma et al do not disclose composites having mechanical properties approaching those of natural soft tissue.
Analogous to rubber which is a three dimensional network of crosslinked polymer chains, poly(diol citrates) are composed of three-dimensional polyester networks formed by reacting citric acid with various aliphatic diols. The mechanical properties could be varied depending on the selection of diols and the applied post-polymerization conditions. In general, longer chain diols have a lower tensile strength and modulus, while increasing polymerization time and/or temperature increase the tensile strength and modulus. Preliminary in vitro cell culture evaluation of poly(diol citrates) showed their great potential as “cell-friendly” materials, as both smooth muscle and endothelial cells attach and proliferate on the surface. Methods of preparation of poly(diol) citrates are described in detail in U.S. patent application Ser. No. 10/945,354 (incorporated herein by reference and also shown in the Examples below). In vivo biocompatibility results show a thin vascularized collagenous capsule after 4 months of implantation with no inflammation. The thickness of this capsule was smaller than that reported for poly(L-lactide-co-glycolide) (PLGA) [17]. A thin vascularized capsule is considered to be beneficial for mass transfer between a cell-based implant and surrounding tissues.
Although the mechanical properties of synthetic polymers, in particular poly(diol citrates), can be varied to meet specific applications, it can be desirable to further increase the strength and stiffness while maintaining the ability to be elongated to many times their original length before rupture. The present invention is directed to optimizing the strength and elasticity of biocompatible scaffolds by preparing a composite comprising an elastomeric polymer strengthened by the presence of a biodegradable polymeric nanostructure.